All publications mentioned throughout this application are fully incorporated herein by reference, including all references cited therein.
Bone Strength
Traditional Dual X-ray Absorptiometry (DEXA) is a crude expression of bone mineral concentration for a given area. It is limited to measuring one property of the bone only, Bone Mineral Density (BMD), also known as Bone Mass. DEXA does not take into account properties such as bone size or bone architecture. BMD is also influenced by body mass and growth.
Bone strength reflects several varied bone properties and provides a more complete picture of the bone's fragility, as compared to bone density.
Speed of Sound (SOS) is the most appropriate technology to measure bone strength. The propagation of sound waves in bone [Speed of Sound (SOS)] is determined by a number of factors including: mineral density, cortical thickness, elasticity and micro-architecture; thus, possibly providing a more complete picture of bone strength than by measurements of bone density alone.
Bone architecture is defined by the pattern of trabeculae and associated structures. Bone structure is also defined by what is known as “Wolff's law”, which determines that: “Every change in the form and function of a bone, or in its function alone, is followed by certain definite changes in its internal architecture and secondary alterations in its external conformation”.
General
Osteoporosis is defined by health care professionals today as “a pediatric disease with geriatric consequences”. This position has led to a strong focus on the development of healthy bones during infancy, childhood and adolescence, and is expected to contribute to a decrease in the incidence of osteoporosis among tomorrow's adults.
Researchers agree that an individual who does not reach optimal peak bone strength during childhood and adolescence may develop osteoporosis later in life, even if he does not suffer from accelerated bone loss. With many children at risk for less-than-optimal bone development because of limited physical activity, poor nutrition, or other risk factors, the measurement of bone in infancy and childhood is invaluable for ensuring that children develop optimal peak bone strength by adulthood. Special populations at risk for poor bone development include children born prematurely, obese children, and others, who can especially benefit from early assessment of bone development.
A large collection of clinical evidence shows that children's lifestyles can impact in their bone development and affect their skeletal health for years to come. Both lifestyle and nutrition have a significant impact on bone during skeletal development and growth. By the end of adolescence, an adult has accumulated most of the bone that will bring him to maximal peak bone strength. This peak determines the starting point for the decline of bone strength in late adulthood. Along with subsequent bone loss, it will determine a person's risk for osteoporosis later in life.
The impact of all of these lifestyle factors on bone health emphasizes the importance of positive factors improving bone strength or status during these crucial years of infancy and childhood. There is a growing trend among health professionals to urge children and adolescents to adopt an overall healthy lifestyle to help bone reach its maximal strength peak.
Preterm Infants
Despite a steady decline in live birth rates in the United States over the past two decades, the incidence of preterm births (infants born at less than 37 weeks of gestation) is increasing. Metabolic bone disease is a relatively common event in preterm infants because the major period of bone mineral accretion ordinarily occurs during the last trimester of pregnancy, and it is difficult to reproduce in the extra-uterine environment.
Pre-term infants, or premature infants, are classified according to their weight as AGA (appropriate for gestational age) or SGA (small for gestational age). In addition, infants are also classified as LBW (low birth weight, born with less than 2.5 kg), VLBW (very low birth weight, born with less than 1.5 kg), or extreme VLBW (born with less than 1 kg).
Premature infants, especially small (for date) premature infants, are susceptible to metabolic bone disease of prematurity (NIBDP). The degree of osteopenia is inversely related to weight and gestational age. There are data showing that fractures are detected in 10-20% of newborns with a birth weight of less than 1,500 g and gestational age less than 34 weeks. Very low birth weight (VLBW) infants have an increased risk of osteopenia because of limited accretion of bone mass in utero and a greater need for bone nutrients. The prevalence of osteopenia is estimated to be 50% in infants born at extreme low birth (ELBW) with a high fracture rate. Severe morbidity during the neonatal period, development of bronchopulmonary dysplasia, chronic treatment with diuretics and steroids, prolonged immobility and the need for total parenteral nutrition increase the risk of impaired bone health. This emphasizes the essentiality and crucial importance of a high quality and bone strength improving formula.
The rising incidence of preterm births, coupled with their improved survival as a result of highly evolving technologies, has placed an increased need to develop more innovative and cost-effective treatment modalities for preterm infants during the neonatal period and in later life. Pre-term babies do not achieve the bone strength normally accreted during the third trimester of pregnancy, and are often born with low bone strength. Preterm infants, infants born to diabetic mothers, and infants exposed to corticosteroids are considered at risk for compromised bone health.
Most therapeutic efforts to prevent osteopenia of premature infants have focused on nutritional changes in the content of calcium and vitamin D. However, despite the use of mineral-enriched special formulas, these efforts have been only partially successful in improving preterm infants bone mineralization. Again, this may reflect the fact that efforts have focused on quantitative, rather than qualitative changes.
Although prevention of osteopenia is the ultimate goal, identifying infants with existing bone deficiencies would facilitate early interventions such as dietary modifications, exercise programs, or medications.
Bone strength follow up enables tracking of neonate bone. On basis of the results of such tracking, pediatricians/dietitians may recommend quality formulas or other foods for underdeveloped infants/toddlers/children in order to achieve or maintain stronger bones.
Children
Most of the skeletal strength is accrued by the age of 18 years, making bone growth during childhood and adolescence a critical process. Moreover, failure to achieve peak bone strength during this critical period cannot be compensated for later in life. This results in an increased risk of osteopenia and fractures in the future. Pediatricians are in a critical position to affect bone development and prevent behaviors and habits that may lead in the long term to fracture risk and osteoporosis in their patients.
Bone strength and bone development are affected by some important factors that are also important for maintaining bone health. Calcium is one of the main mineral components of bone, supplying density and stiffness to the skeleton, and it is therefore an important factor in maintaining bone health. Recommendations suggest that children and adolescents should increase their calcium intake considerably above present average levels, to ensure adequate development of bone. The diet of many presumably healthy children contains inadequate amounts of dairy products, green vegetables, and other calcium-rich foods. Regular physical activity is another significant factor in bone development. Studies have shown that regular exercise helps strengthen bones. Exercise causes muscles to contract against bone, exerting force on the bone, and strengthening it. Current recommendations include moderate physical activity on most days of the week.
Various other factors are also known to be associated with a negative effect on bone status and the eventual development of osteoporosis. Among these factors are repeated dieting which leads to anorexia nervosa, smoking, alcohol consumption, and intake of carbonated soft drinks. Over-exercising that leads to amenorrhea, a frequent problem of some professional athletes, can also lower bone strength.
Further, children born pre-term or at a low birth weight have low bone strength values for at least six years after birth, indicating an increased risk for weak bones well after infancy. This is probably a result of the high prevalence of Osteopenia of Prematurity in premature infants.
Prior art publications suggested special compositions and methods for increasing bone density and peak bone mass. For example WO05/036978, incorporated herein by reference, discloses an enzymatically prepared fat base composition comprising specific vegetable-derived triglycerides, its preparation and various uses in the field of infant formulas, for preventing calcium and energy losses. US Patent Application No. 2004/0062820 discloses a method for increasing bone mineralization employing a fat blend that is low in palmitic acid.
However, as described above, in order to provide for the development of healthy bones and skeleton, it is important to ensure sufficient bone strength, not only adequate calcium absorption, bone density and bone mass. Bone density, peak bone mass and/or bone mineralization are not always in accord with bone strength, and changing any or all of the first (i.e., bone density, peak bone mass and/or bone mineralization) does not necessarily result in a corresponding change of the latter (bone strength). This notion has been supported by various authors, including Majumdar [Majumdar S. (2003) Curr. Osteoporos. Rep. 1(3):105-9], Turner [Turner C. H. (2002) Osteoporos. Int. 13(2): 97-104], and Gilsanz [Gilsanz V. (1998) Eur. J. Radiol. 26(2):177-82]
Amongst the studies reporting the absence of correlation between bone density and bone mineralization and bone strength, it may be cited for example the study by Takeda and colleagues [Takeda et al. (2004) J. Amer. Coll. Nutr. 23(6):712S-714S] who described the relationship between bone strength and bone mineral concentration in obese rats and concluded that variation in elemental concentrations was not correlated with bone strength. Riggs and colleagues showed that in post-menopausal women, fluoride treatment increased bone mass and concomitantly increased skeletal fragility, particularly of non-vertebral bones [Riggs et al. (1990) N. Engl. J. Med. 322(12):802-9]. Divittorio et al. reached a similar conclusion [Divittorio et al. (2006) Pharmacotherapy 26(1):104-14]. In contrast, raloxifene, a selective estrogen receptor modulator, significantly improved vertebral bone strength independent of bone mineral density [Allen et al. (2006) Bone 39:1130-1135].
Increase in bone strength reflects lower liability to fractures and other mechanical bone defects.
It is therefore an object of the present invention to provide compositions and methods for increasing and maintaining bone strength in newborns, infants, toddlers, children and adolescents.
It is a further object of the invention to provide compositions and methods for improving and maintaining bone status in humans.